B6 and phenols. Finally, an explanation!

Enzyme Stuff discussion on excessive B vitamins

Sometimes parents are advised to give very excessively high doses of B6 for their children with autism spectrum conditions. However, experience shows that many children have very terrible reactions to supplements with excessively high doses of B6. The ARI information from over several decades also shows that the majority of people with autism do not benefit from high B6 vitamin supplements although some do. A high does is about 50 mg, a very high dose 100 mg, and excessively high often way over that. While some B6 as well as other basic vitamins are beneficial, excessive amounts may be too much neuro- stimulant particularly for neurologically sensitive people. It is important to check with a qualified medical doctor for your situation when taking anything over the Recommended Daily Allowance of anything.

Why so many negative reactions and why might some do okay with it? For one thing, most all sources agree that B vitamins work as a team together and should be taken in the proper ratios - a balance of B vitamins. Taking an excessive amount of just one or two individual vitamins in the B family can cause deficiencies in other B vitamins. So you might just be trading one problem for another.

Another problem is that many synthetically made B6 vitamins may be made from coal-tar. Coal-tar derived synthetics include artificial colorings and flavorings. So if someone has a sulfate processing problem, or is sensitive to artificial additives of this nature, or doesn't tolerate phenolic compounds or artificial additives, then they may very likely not tolerate B6 vitamins if they are synthetically derived. If you are not tolerating B vitamins, you might want to look at a non- synthetic source of nutrients. More information and several non-synthetic formulations are at the link below. In the middle of this page are some links that go to research showing why taking lots of synthetic supplements is not always the most healthful, and you might want to try getting as much nutrition from natural sources as possible. Nutrition and enzymes (general diet strategies)

Phenols and PST

This is a LONG discussion on the phenol-sulphotransferase issue, but
it is very informative and I recommend you print it out and study it
if you think your child might have this problem.

This is a condition that affects 80% to 90% of the children with
autism. It is vital that you understand the symptoms, and if they
affect your child, you must "unload the donkey". PST (phenol-
sulfotransferase) is a Phase II enzyme that detoxifies leftover
hormones and a wide variety of toxic molecules, such as phenols and
amines that are produced in the body (and even in the gut by
bacteria, yeast, and other fungi) as well as food dyes and chemicals.
These reactions include the breakdown of bilirubin and biliverdin,
which are the breakdown products of hemoglobin. There are many
varieties of phenols. This may indicate why children's intolerances
vary. Remember, Bolte notes that tetanus infection of the intestines
leads to the formation of toxic phenols, and states that these are
particularly formed by overgrowth of the Clostridium family of
bacteria. The toxins formed can peel the lining of the colon right
off the organ, and lead to an explosive, debilitating form of
diarrhea. She notes that tetanus also attacks the Purkinje cells of
the brain potentially reducing the production of the amino acid GABA,
a calming neurotransmitter known to affect speech.

"The PST enzyme is only one of many sulfotransferases, and various
other body chemicals can increase the quantity of some
sulfotransferases, and that would increase their activity....Sulfate
must be grabbed by any sulfotransferase before the enzyme can attach
it to something else, like phenols or MHPG (3 methoxy-4-
hydroxyphenylglycol, a natural breakdown product of a class of
neurotransmitters called catecholamines). If the PST enzyme activity
towards something is low, you can boost it by two approaches. The
first is to increase the amount of sulfate available to it. The
second is to increase the amount of the enzyme so it has an easier
job finding the available sulfate."-Susan Owens.

The PST enzyme links an oxidized sulfur molecule (a sulfate) to these
various toxic substances to solubilize them so the kidneys can
dispose of them. Obviously, if sulfate is low or missing, this can't
happen effectively. Hence, the problem can be twofold: there may be a
lack of phenol-sulfotransferase enzymes, or of the sulfates (due to
the absence of protein and of sulfur carrying raw vegetables in the
diet, the poor absorption of sulfur from the diet, a failure to
metabolize sulfur into sulfate form, or increased urinary excretion
of sulfite and sulfate).

Dr. Rosemary Waring's research shows that the lack of sulfate is the
primary problem in 73% of these children (another study found low
levels in 92%), but all of those Waring checked had a low PST level
too. Similar sulfate deficiencies have been reported in people with
migraine, rheumatoid arthritis, jaundice, and other allergic
conditions all of which are anecdotally reported as common in the
families of people with autism. Adequate sulfoxidation requires
adequate supplies of B-vitamins, especially vitamin B6. The PST
enzymes are inhibited or overloaded by chocolate, bananas, orange
juice, vanillin, and food colorants such as tartrazine. Removal of
these from the diet and supplementation of sulfates may well relieve
all these symptoms. The lack of sulfation could well be due to the
largely carbohydrate diet of most of these children. It is likely a
combination of all these things. In any case, toxic compounds of
these aforementioned chemicals can build to dangerous levels. A high
value for the tIAG (?) as well as a high reading for DHPPA (rather
HPHPA-a phenolic metabolite of tyrosine) both indicate a PST problem.

There are two pathways by which the Phase II enzymes process these
toxins. One attaches the sulfates as mentioned, and the other
attaches glucuronide. Dr. Waring has found that in autistic patients
there is not nearly enough sulfate to glucuronate ratio. She and her
associates feel that the "leaky gut", that causes a need for a Gf/Cf
diet, is caused by this lack of adequate sulfate to provide sulfation
of the glucosaminoglycans (sulfated sugars). They found that the
glucosaminoglycans (gags) in the gut were very under sulfated, and
that this causes a thickening of the basement membrane of the gut.
IGF (insulin-like growth factor) is important for cell growth. IGF-1
(which is reduced in zinc deficiency) increases the incorporation of
sulfate in glucosaminoglycans.

Unfortunately, a lack of sulfated gags in the kidneys will allow loss
of these sulfates. There is often found low plasma sulfate and high
urine sulfate and high urinary thiosulfate as if the kidneys are not
able to retain (recycle) sulfate. This needed retention requires the
work of a transporter that has been found in "in vitro" studies to be
blocked almost completely by mercury and by excess chromium (but not
as thoroughly). One study found urinary sulfite to be elevated due to
a lack of molybdenum in 36%. Supplementing moly showed improvements
in clinical symptoms. Sugar increases the amounts of calcium,
oxalate, uric acid, and glucosaminoglycans being wasted in the urine.

Sulfates have a negative charge and repel each other, so that charge
forms a barrier on the outside of the cell called the matrix, or the
glycocalyx. Sulfate is often found in the glycoprotein film also.
Glycoprotein is a sugar/protein film that enables cell-cell
communication. This film is on all cells of the body, so if systemic
sulfate is low, you most likely have a big problem that is quite
general to the whole body. Specifically, the more densely sulfated
the GAGs, the more they can resist all kinds of infection. These
sulfate molecules govern or influence the ability of the cell to
produce its unique set of specialized proteins. It is not something
you want to be operating from a deficit, yet that is the condition of
most autistic children.

Dr. Waring found that 92% of autistic children seem to be wasting
sulfate in the urine; for blood plasma levels are typically low and
urinary levels are high. There is also an abnormal cysteine to
sulfate ratio. Cysteine is the amino acid that should be used to make
sulfate, so it appears that the sulfate is probably being utilized
far faster than the cysteine can be converted, leaving a deficit of
sulfate (sugar wastes it), or the cysteine is not being metabolized
to sulfate. That may cause the cysteine to build up to toxic levels.
Cysteine is formed from the essential amino acid methionine.
Homocysteine, an intermediate between methionine and cysteine, and
cysteine are powerful excitotoxins. In the aged, and in chronic
disease, methionine is not efficiently converted to cysteine, but
builds homocysteine. This can create a deficiency of this vital amino
acid, cysteine, and a lack of sulfate. A deficiency of cysteine, or a
failure to metabolized it to sulfate, will produce multiple chemical
sensitivities and food allergies. Being a major part of the powerful
antioxidants alpha lipoic acid and glutathione, a deficiency of
cysteine, or a failure to metabolize it into these antioxidants,
would greatly affect the liver's ability to detoxify, and would lead
to destruction throughout the body by free radicals This would also
allow buildup of the heavy metals lead, cadmium, mercury, and
aluminum. Supplementation of vitamin B2, B6, B12, folic acid,
magnesium, and TMG may normalize metabolism of methionine into
cysteine, but vitamin C is needed to prevent cysteine (which
contributes its sulfur more readily) from converting to cystine, its
oxidized form.

What could be one source of interference with sulfation? Swimming!
High concentrations of chlorate were detected in samples from a
number of pools; in one case as high as 40 mg/l. Higher chlorate
concentrations were associated with those pools using hypochlorite
solution as a disinfecting agent, while relatively low chlorate
concentrations were found in pools treated with gaseous chlorine.
Chlorate IS the biological substance of choice to block sulfation.
Additionally, chlorate is known to inhibit hematopoiesis [the making
of new blood cells], a problem with many of our kids. Additionally,
hypochlorite reportedly combines with any phenolic compound, even in
very dilute solutions, to form an aromatic compound that can react in
the body. This combining of chemicals can be very toxic to
susceptible individuals. One Mom found that an Epsom salts bath
immediately following eliminated after swimming problems in behavior.
So, if you must swim, do the bath immediately after coming from the
pool. For home pools, one Mother reports, "An ionizer cuts down
chlorine use by 70-80%. Since installing this, we don't see the
reactions anymore."

The excess-cysteine/low-sulfate condition that Waring observed may be
because of a deficiency of the amino acid histidine that can be run
low by seasonal allergies and the medications taken to treat them.
Metal toxicities, common in these kids, can run it low. Experimental
deficiency of histidine causes an excess of free iron in the blood.
This can adversely affect the enzyme cysteine dioxygenase (CDO), the
essential nutritional components of the enzyme being histidine and
iron. A deficiency of this amino acid, possibly caused by allergies,
heavy metals poisoning, and medications, not only affects HCl
production (histidine delivers zinc to the cells, and together they
produce HCl), but it will likely cause a toxic build up of the amino
acid cysteine, and a lack of sufficient taurine and sulfate
contributing to the PST problem. High histidine lowers zinc and
copper by chelating them from the body. Supplementing taurine, the
sulfur containing amino-acid that is at the end of the metabolic
chain, has been helpful in meeting this need for taurine; and, being
the immediate precursor, may supply needed sulfates. Taurine is
reported to have an anti-opioid effect (Braverman 1987).

Those with inadequate protein in the diet, or with poor assimilation,
resulting in a deficiency of histidine and other nutrients, form
poorly sulfated GAGS robbing the cells of ability to resist infection
(that describes 100% of these children). Additionally, it produces
dysbiosis (flora imbalance) in the gut. Those with chronic infection
shed and replace GAGs so quickly that inadequate sulfate is available
even with adequate protein intake. Vitamin A deficiency has been
shown to produce an accelerated turnover of GAGs as well as their
undersulfation. When the live viral, measles vaccine is given, it
depletes the children of their existing supply of Vitamin A. The
measles virus hidden in the gut is able to create a chronic vitamin A
deficiency. Natural Vitamin A (cis form) is important for activation
of T and B cells for long-term immune memory to develop, and it is
necessary for optimal Natural Killer Cell function, Cis Vitamin A can
bypass blocked G-protein pathways and turn on central retinoid
receptors. Available zinc controls the amount of vitamin A the liver
will release.

In one study, the urinary GAGs changed to normal when the vitamin A
deficiency was corrected, but if protein starvation caused the
undersulfation of GAGs, the urinary GAGs did not return to normal
with adequate protein intake, but did improve quite a bit. Most
autistic children are vitamin A deficient. Do you or your child have
bumps on shoulders, thighs, elbows, and calves? Supplement with pure
amino acids, Seacure™, Brewer's yeast, or desiccated liver for their
protein, and with Evening Primrose oil (for its GLA), and cod-liver
oil for its EPA, DHA, and vitamins A and D. Seacure™ may help.

It was Dr. Andrew Wakefield's work that showed that at the core of
the problem might be an inflammation of the gut caused by a chronic
measles infection. Dr. Wakefield's work is being vindicated by other
researchers. Under oath before Congress on April 6, 2000, Professor
John O'Leary told how his state-of-the-art laboratory had identified
the measles virus, something that certainly should not have been
there, in samples taken from the intestines of 24 of the 25 patients.
From Japan: "The sequences obtained from the patients with Crohn's
disease shared the characteristics with wild-strain virus. The
sequences obtained from the patients with ulcerative colitis and
children with autism were consistent with being vaccine strains. The
results were concordant with the exposure history of the patients.
Persistence of measles virus was confirmed in PBMC (blood cells) in
some patients with chronic intestinal inflammation"-Kawashima H, Mori
T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A, Department of
Paediatrics, Tokyo Medical University, Japan. From Canada: "The
presence of measles virus in the brain tissue was confirmed by
reverse transcription polymerase chain reaction. The nucleotide
sequence in the nucleoprotein and fusion gene regions was identical
to that of the Moraten and Schwarz vaccine strains; the fusion gene
differed from known genotype A wild-type viruses"-Bitnun A, Shannon
P, Durward A, Rota PA, Bellini WJ, Graham C, Wang E, Ford-Jones EL,
Cox P, Becker L, Fearon M, Petric M, Tellier R; Department of
Critical Care Medicine, The Hospital for Sick Children, Toronto,
Ontario, Canada. Clin Infect Dis 1999 Oct;29(4):855-61. From
Sweden: "This study provides evidence that measles virus can spread
through axonal pathways in the brain. The findings obtained in the
gene-manipulated mice point out that a compromised immune state of
the host may potentiate targeting of virus to the limbic system
through olfactory projections"-Urbanska EM; Chambers BJ; Ljunggren
HG; Norrby E; Kristensson K, Department of Neuroscience, Karolinska
Institute, Stockholm, Sweden.

The gut sheds sulfated glucosaminoglycans during inflammation which
could account for the low levels there and the high levels in urine.
This leads to a "Leaky Gut" condition, and to the excess opioid
problem. Not only do macrophages (scavenging white blood cells) eat
GAGs and release inorganic sulfate, there is a transporter the
intestines use to absorb sulfate from the diet, called the DRA
transporter. Its levels will decrease five-to-seven fold when the gut
is inflamed. That would make it extremely difficult to absorb
adequate sulfate from food or from oral supplements. The problem is a
nutritional one, but it is not one easily solved by oral
supplementation of a missing substance. The gut must be healed.

Since sulfur intake is low, and its oxidation is slow in many
autistic children, sulfate is low, and PST activity is slower than it
would be otherwise. It would seem that this sub optimality of
sulphotransferase activity is a function of low plasma sulfate levels
rather than of deficits in the actual enzyme. Cellular level
enzymatic effects of mercury's binding with proteins include blockage
of sulfur oxidation processes and of the neurotransmitter amino
acids. These have been found to be significant factors in many
autistics. Thus, mercury, and any foodstuff that requires or uses up
sulfate ions during its metabolism, will make the situation worse.
These foodstuffs include foods that supply neurotransmitters, like
bananas (serotonin), chocolate (phenylethylamine), and cheese
(tyramine), apple juice (and one mother reports her child drank a
quart a day!), citrus fruit juices, and paracetamol (Tylenol™). For
instance, one or two minutes after a dose of Tylenol™, the entire
supply of sulfate in the liver is gone!

In fact, any chemicals with a high proportion of phenolic groupings
will have this effect, and will enhance the problems referred to
above. Many coloring materials, whether of natural or synthetic
origin, possess phenolic groupings. Phenol, an organic compound, has
other names such as hydroxybenzene. If the PST enzyme is deficient or
sulfoxidation is lacking in some 70% to 80% of autistic kids as some
say, it behooves mothers to seriously heed the information in this
section, and to carefully guard their children from certain obvious
sources of trouble.

It is interesting to note Dr. Waring's statement that those with the
PST/low sulfation problem have central nervous system problems from
the toxic amines. For example migraine sufferers usually have low PST
activity, and are readily affected by dietary "triggers", especially
those with amines. Compounds such as flavonoids (red wine and citrus
fruits), aged cheese, beers, chocolate, and strong odors inhibit PST
leading to headache in the less resistant. Apple juice, citrus
fruits, chocolate, and paracetamol (Tylenol™) were precisely those
that were known to precipitate migraine attacks in susceptible
individuals. It should be noted that many multivitamin supplements,
grapeseed extract, Pycnogenol™, Quercetin, and other antioxidants
contain high amounts of flavonoids. Quercetin is found in 78% of the
foods. It is useful in hay fever (suppress the histamine release),
some forms of cardiovascular disease, and it chelates metals to
prevent oxidation. It decreases vascular fragility, but stimulates
adrenaline release (decreasing thymus weight), reduces general
metabolism (reduces temperature and oxygen consumption), suppresses
thyroid activity, inhibits p450 (Phase I) liver enzyme activity, and
it is linked with male impotence. From this list of negatives, one
can see it should not be used in quantity for long term.

Modifications of serotonin (5-HT), dopamine (DA), and DA metabolites
[homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC)] were
assessed at urinary levels. Responders and nonresponders showed a
significant decrease of urinary 5-HT levels on fenfluramine (appetite
suppressant related to amphetamine). The main differences between the
two groups of subjects were found with HVA, the major metabolite of
dopamine. Fenfluramine (an amphetamine) significantly increased HVA
levels in responders whereas no significant modification was found in
nonresponders. Moreover, the initial level of HVA (lower in
responders) significantly differentiated the two groups. These
results suggest that the clinical response to fenfluramine could be
related to the dopaminergic action of this drug and that urinary DA
metabolite levels could be considered as indicators of the
responsiveness to fenfluramine treatment in children with autistic
behavior-Barthelemy C; Bruneau N; Jouve J; Martineau J; Muh JP;
Lelord G Source: J Autism Dev Disord, 1989 Jun, 19:2, 241-54. Drugs
such as Ritalin™ and ADDerol™ affect dopamine activity, and thus
stimulate the part of the brain that monitors the arousal system,
resulting in better regulation. There are safer ways to build
dopamine than psychostimulants, amphetamines and alcohol. In France,
scientists found administration of NADH (ENADA™) caused more than a
40% increase in production of dopamine and norepinephrine, which are
vital for strength, coordination, movement, cognitive function, mood,
and sex drive (Birkmayer 1996). The amino acid tyrosine builds
dopamine and norepinephrine also.

"... dopamine sulphotransferase (ST) activity was inhibited strongly
by (+/-)-catechin, (+)-catechin, octyl gallate, tartrazine (yellow
#5), and vanillin (synthetic vanilla). Sulphation of the xenobiotic
steroid (foreign to the body) 17 alpha-ethinyloestradiol (EE2) was
inhibited by vanillin, erythrosin B, and octyl gallate [antioxidant
used in margarine]....Vanillin was found to inhibit 50% of liver EE2
ST activity ..."-Common Food Additives are Potent Inhibitors of Human
liver 17 Alpha-ethinyloestradiol and Dopamine Sulphotransferases.-
Bamforth KJ, Jones AL, Roberts RC, Coughtrie MW, Biochem Pharmacol
1993 Nov 17;46(10):1713-20.

There are a number of consequences attributable to PST/sulfate
deficiency including effects upon the impaired breakdown and
metabolism of classical neurotransmitters such as serotonin and
dopamine; impaired breakdown and metabolism of the bile pigments
bilirubin and biliverdin; impaired action of the hormone CCK on CCKA
receptors which would result in decreased secretion of pancreatic
enzymes and of bile from the gall bladder and biliary tract into the
intestines. This would result in low uptake of certain vitamins and
other nutrients from the intestines; reduced activity of gastrin (and
subsequent reduced secretion of stomach acid, mucus, and pepsin in
the stomach), and, probably, reduced production of secretin farther
downstream. Secretin (esp. at high concentrations) inhibits the
histamine releasing action of gastrin and pentagastrin reducing HCl
as the stomach empties.

Because there is a lack of serotonin available to the brain, which
causes many of the most distressing symptoms of autism, it seems
reasonable to build the available serotonin by providing its
precursor 5-HTP. The use of 25-50 mg three or four times a day
(unless it causes a drowsiness that interferes with school) should be
most beneficial. If drowsiness interferes with school, reduce the
amount and/or give it later in the day. Giving 100 mg one to four
hours before bedtime has safely improved the sleep of many.
Nevertheless, a PST child may not tolerate it. If hyperactivity or
sleeplessness is observed, please discontinue.

Those with these PST deficits cannot readily excrete the phenols,
amines, and other listed toxic substances. These substances are
strongly acidic, and they exert toxic effects in the brain, where
normally certain enzymes prevent their accumulation. They build up to
abnormal levels and interfere with the neurotransmitters serotonin,
dopamine, and noradrenaline among other things. Symptoms of
PST/sulfate deficiency are excessive thirst, normal urination, night
sweats, odorous bed clothes, black eye shadows, facial flushing, and
red ears. These vary with the degree or level of toxic buildup.
Certain foods may cause fevers, and some, especially those taking
Paracetamol™ (Tylenol™), may go up to 24 hours without urination.

A phenolic compound may cause a variety of different symptoms in
various individuals. There is evidence of immune suppression on
exposure to testing doses of phenolics. There may be a drop in T-
suppressor cells or total T-cell numbers. An overabundance of B-cells
was interpreted as a reflection of toxic image to the immune system.
An increase in helper cells, antibody formation, and elevation of
some immunoglobulins was also noted. Other findings on phenolic
exposure have been depressed serotonin, elevated histamine and
prostaglandins, abnormal complement and immune complex formation.
These compounds can contribute to the toxic overload in PST, or they
can precipitate an allergic reaction.

Neurologic symptoms: In severe phenol poisoning, initial signs and
symptoms may include nausea, diaphoresis (heavy perspiration),
headache, dizziness, and tinnitus (ringing ears). Seizures, coma,
respiratory depression, and death may ensue quickly. Coma and
seizures usually occur within minutes to a few hours after exposure
or after a delay of up to 18 hours. Phenol also may cause
demyelination and axonal damage of peripheral nerves. Typically,
transitory central nervous system (CNS) excitation occurs, then
profound CNS depression ensues rapidly. Metabolic acidosis and acute
renal failure may complicate the condition. Vomiting and diarrhea are
common effects of phenol toxicity by any route. Peristalsis is
increased in the intestine and distribution of blood is altered by
these phenolics because of sensitizing smooth muscles to epinephrine,
norepinephrine, and other physiological stimulants.

Nutritional deficiencies will affect the body's ability to detoxify
foreign chemicals. For example, magnesium is important in over 300
enzyme systems that relate to Phase and Phase II detoxification;
however, the average American diet is low in magnesium. The Phase I
enzymes alcohol dehydrogenase and aldehyde dehydrogenase are zinc
dependent, and NAD, the coenzyme form of niacin, activates these two
enzymes that break down alcohol and acetylaldehyde (AH). Magnesium
and NAD are both dependent on adequate supplies of vitamin B6, in the
form P5P. Aldehyde oxidase requires molybdenum. A deficiency of P5P,
NAD, zinc, magnesium, molybdenum, or the amino acid histidine could
significantly impair the ability to detoxify those chemicals,
especially the toxins of candida (acetylaldehyde).

By supplementing molybdenum and histidine (needed in the molybdenum-
histidine containing enzymes, sulfite oxidase and cysteine
dioxygenase, that oxidize sulfur), along with iron, and the B-complex
(preferably in coenzyme form), glucosamine/chondroitin sulfate
(stimulates synthesis of the GAGs we studied about above, and is
mildly anti-inflammatory without inhibiting the synthesis of
Prostaglandins, and more effective when taken together), minerals in
sulfate form, such as iron sulfate, and Epsom salts (magnesium
sulfate-taken orally it is a good laxative for those that need it),
one may supply both the minerals and the sulfate needed to detoxify
phenols and other metabolites. When glucosamine gives up its sulfate,
it supplies glutamine. Chondroitin is comprised of N-acetyl-D-
galactosamine and D-glucuronate. Collagen Type II™ may be even better
for it supplies at least 50 other types of sulfate such as heparan,
keratan, and dermatan sulfate. Curiously, bread is sulfate rich. This
program will increase the number and enhance the efficiency of the
available PST enzymes in doing their job.

Buy a quality brand (one using Good Manufacturing Practices) of
glucosamine/chondroitin sulfate that uses low molecular weight
ingredients the use of which will supply adequate GAGs to enable the
cells to resist infection. There are 4 different methods of
manufacturing glucosamine capsules. According to sources at Jarrow
Formulas, both glucosamine hydrochloride and N-Acetyl-glucosamine
have been stripped of the "sulfate" component in the manufacturing
process. Neither of these forms are expected to have any anti-viral
effect against lipid envelope viruses like HIV, EBV, CMV and HHV-6,
and of course, they would not supply needed sulfate for PST.
Published scientific research indicates that only the sulfated
polysaccharides and one sulfated monosaccharide (glucosamine sulfate)
have a powerful effect against lipid envelope viruses. If the
word "hydrochloride" or "N-Acetyl" appears anywhere on the label, do
not buy it unless you are planning to use it exclusively for
arthritis or rheumatism. Remember to choose capsules instead of
tablets.

In addition, take an Epsom salts bath (two cups or more in a tub of
hot water). It may be best not to use soap as there may be chemical
reactions that could be adverse. Soak it up through the skin for 20
minutes, and don't rinse off-and don't worry if the child drinks some
of the water. This bath has been shown to increase sulfur content of
the blood up to four times. Sleep is improved immediately, as the
child is relieved of pain and calmed.

I should mention that there is a small chance of magnesium toxicity.
Decreasing kidney function, common in the elderly, may prevent
magnesium from being excreted normally leading to a toxic condition.
Initially, symptoms include: drowsiness, lethargy and weakness. At
higher levels, nausea, vomiting, and serious arrhythmia (irregular
heart beat) may occur. If this be the cause of these symptoms, they
will disappear quickly once the use of magnesium bearing products is
discontinued. -Dr. Richard M. Ratzan, University of Connecticut
Health Center. This could only occur with very poor kidney function
for the toxic level is approximately 6000 mg daily. If there has been
any indication that the child's kidneys are not functioning fully
(possibly high creatinine levels), check with your doctor before
using magnesium (or potassium), and have him monitor
magnesium/potassium levels. Strive for high normal levels. Adequate
potassium stimulates the kidneys to excrete poisonous body wastes
(usually toxic protein acids from inadequate protein digestion).

Be sure to filter chlorine, fluoride, and other poisons from the
water you drink and bath in. Chlorine in bath water is breathed and
absorbed, especially from hot water. This is important as chlorine is
a deadly poison. It can produce fatigue and tiredness after the bath.
Industrial chemist, J.P. Bercz, Ph.D., showed in 1992 that
chlorinated water alters and destroys unsaturated essential fatty
acids (EFAs), the building blocks of people's brains and central
nervous systems. The compound hypochlorite, created when chlorine
mixes with water, generates excess free radicals; these oxidize EFAs,
turning them rancid. Both chlorine and fluoride inhibit the stomach's
ability to produce HCl, and impair the ability of beneficial flora to
grow in the gut. Do not buy a filter that uses silver as a
bactericide. It is known to leak into the water and elevate levels in
the blood dangerously.

While taking a warm shower or lounging in a hot tub filled with
chlorinated water one inhales chloroform. Even worse, warm water
opens the pores, causing the skin to act like a sponge. One will
absorb and inhale more chlorine in a 10-minute shower than by
drinking eight glasses of the same water. This irritates the eyes,
the sinuses, throat, skin and lungs, makes the hair and scalp dry,
worsening dandruff. It can weaken immunity. A window from the shower
room open to the outdoors removes chloroform from the shower room
air, but to prevent absorption of chlorine through the skin, a shower-
head that removes chlorine from shower water is a must. The
ShowerWise™ filter and shower head can be ordered for $69, plus two
filters $129. They last about one year. An extension hose can be used
to fill the tub with filtered water.

For those times when the bath is not convenient (camping), or when
one wants to increase the amount of magnesium, but bowels are
sensitive to it, one can have the benefits of the bath with a cream.
Kyle, for whom it was developed, prefers the cream. Rub 1/2 teaspoon
of the cream on the tender parts to obtain 250 mg magnesium. The
cream is especially formulated by Key Pharmacy, 1-800-878-1322 or 1-
416-633-2244, FAX: 1-416-633-3400. Ask for the Epsom Salts Cream. A 4
oz. jar for $29.89, plus shipping, has approximately 48 servings. All
ingredients seem safe for our children, for it contains fatty acids,
a form of lecithin, and magnesium sulfate. The use of the cream
should avoid the following possibility.

One researcher makes this observation, "I have no doubt that sulfate
is a substrate to feed (some strains of) candida. It probably takes
some energy from the SO4 form and excretes it as H2S, and robs the
energy it may be able to get from reducing the sulfur, excreting
toxic H2S." H2S is very foul smelling, so if an increased foul-
smelling gas is created in following these recommendations, you will
need to deal with the yeast overgrowth.

Sulfate is the most oxidized form of sulfur. It doesn't need to be
oxidized any more, so supplementing or bathing in sulfate supplies
what is lacking because of the body's inability to oxidize the sulfur
in foods. Oral sulfate will be poorly absorbed; so, supplement a gram
or more of sulfate each day. Some will get through. Supplementing
papain enhances absorption of sulfates. SAMe (SAM) is said to improve
sulfoxidation, in fact, it is necessary to the manufacture of all
sulfur-containing compounds in the body. Dr. Jeff Bradstreet, MD,
father of an autistic child, has this to offer: "If the child has an
unusual odor at night or their bedclothes do, or if they sweat while
asleep (PST defect), use methylsulfanylmethane (MSM), 1500 to 3000
mgs per day. In the study, 83% of autistic children were PST
abnormal, and MSM should help this. It did in our son's situation."

MSM works with copper in many functions, and may get depleted with
copper supplementation or when high copper levels are present.
Additionally, our soils are depleted of sulfur, and such sulfonyl as
there is in foods is lost in cooking. MSM is a white, crystalline
powder that is odorless and somewhat bitter tasting. It mixes in
water more easily than sugar, and just barely affects the taste. In
juice or other beverages, it is undetectable. MSM is effective in
ameliorating gastrointestinal upsets such as that produced by the
ingestion of aspirin and other pharmaceuticals, or that from
parasitic infections. Individuals with gastrointestinal symptoms such
as diarrhea, chronic constipation, nausea, hyperacidity and/or
epigastric pain (having been reported more effective than Tagamet™),
or inflammation of mucous membranes also will experience dramatic
relief. Individuals presenting symptoms of pain and inflammation
associated with various musculoskeletal system disorders, including
arthritis, report substantial and long-lasting relief. Those lacking
in sulfite oxidase cannot metabolize MSM, or the sulfite used in
Chinese foods or on some green salads, to sulfate, and may get
headache, dizziness, fatigue, wheezing, leg pain, and other symptoms.
MSM also seems to cause hair loss when there is heavy metals
poisoning, particularly mercury. This may be overcome by
supplementing molybdenum and vitamin B6, and this will enable more
efficient metabolism in this pathway relieving the sensitivity to
sulfur-bearing foods, and producing needed sulfates. Many cannot
tolerate more than 500 mg MSM, yet show very positive benefits from
even this amount. So, start low and increase dosage as you can
tolerate it. Always supplement molybdenum when taking MSM. Two
hundred to 300 mcg a day may be enough, but moly absorbs poorly, and
adults may require 1000 mcg twice daily for three or four months or
longer to overcome this aversion to sulfur-bearing foods.

One should note that mercury binds to the -SH (sulphydryl) groups,
resulting in inactivation of sulfur and blocking of enzyme function,
producing toxicity. Sulfur is essential in enzymes, hormones, nerve
tissue, and red blood cells. Mercury also blocks the metabolic action
of manganese and the entry of calcium ions into cytoplasm. Mercury
thus has the potential to disturb all metabolic processes. Under
these conditions MSM should be most helpful.

DMSO is being used as the solvent in transdermal secretin. This is
essentially the same as MSM. At least one Mom is reported to have
found good results with DMSO alone. When she added secretin further
gains were noted, but when she ran out of secretin, the gains
continued with DMSO alone! DMSO has long had a reputation as a
panacea for about everything that ails you. A case in point, applying
it to the abdomen has alleviated all symptoms of colitis and
Irritable Bowel Syndrome. Both it and MSM work wonders for arthritis.
To avoid skin dryness, dilute it 15% with distilled water.

If the child can metabolize organic sulfur (like MSM/DMSO) all the
way to sulfate, then MSM is a good way of increasing sulfate.
However, if the enzyme sulfite oxidase is not working well, then MSM
is a bad idea. Sulfite oxidase requires molybdenum as a cofactor, and
since mercury depletes selenium; and mercury, MSM, oral sulfate, and
copper tends to deplete molybdenum, selenium and molybdenum must be
supplemented. Conversely, tungsten inhibits the action of molybdenum
and thus of the molybdenum-based enzymes sulfite oxidase, xanthine
oxidase, and aldehyde oxidase. This would likely cause an excess of
molybdenum to accumulate. Thus, both excess mercury and excess
tungsten would create a shortage of the listed enzymes.

A coenzyme, vitamin B-complex supplement of moderate potency should
be supplemented. One mother in supplementing molybdenum reports that
her daughter, who was doing quite well, regressed into severe,
autistic symptoms for three days, including 18 hours of screaming-
possibly due to detoxifying. Her doctor urged her to cease, but she
stayed the course, and today her daughter is far and away better!
This is serious stuff.

Incidentally, a gross deficiency of molybdenum manifests as
tachycardia, headache, mental disturbances, and coma. An excess
intake of 10-15 mg daily (for adults) can cause a gout like syndrome
because of an elevated production of uric acid. Dosage range should
not exceed 1 mg per day (adult), bearing in mind that more than 0.5
mg causes a loss of copper. Very little molybdenum is needed, but it
is an important element in several important metalloenzymes (xanthine
oxidase, aldehyde oxidase, and sulfite oxidase) that participate in
crucial liver detoxification pathways.

Until the body regains its ability to oxidize sulfur, it may be
desirable to limit high sulfur containing foods (cruciferous
vegetables, broccoli, onions, garlic, turnips, eggs, red meat,
turkey, dairy products); and supplements like alpha lipoic acid,
glutathione, L-cysteine, and N-acetylcysteine (NAC can be better
tolerated when used with its team mates, the amino acids glycine and
glutamine in ratio 2:1:1, and the B-complex vitamins. It should be
tried for the glutathione it produces is so vital). Those who have a
problem with these foods likely have an impaired sulfur oxidation (a
cysteine oxidation) problem, and should be alert to cysteine
toxicity. Even those who do not oxidize cysteine well can usually
tolerate NAC at 500 mg daily (adult dose) without contributing to
cysteine toxicity. Supplying any of these sulfur foods may be a
problem to some of these kids who do not oxidize sulfur well. One
indicator may be fatigue after eating these. Unless a problem is
observed, however, these foods should not be restricted unnecessarily
for that will cause a reduction of the vital antioxidant glutathione,
and interfere with the conversion of T4 thyroid hormone into T3.

Blueberry extract, grape seed extract, pine tree bark, Resveratrol,
green tea, and other things have phenols, salicylates, and other
stuff that are normally detoxified by PST.

Some recent studies indicate that salicylate has an effect on PST, an
enzyme needed by the brain and the gut to metabolize high-phenolic
compounds like the artificial colors and flavors. Salicylate
suppresses PST enzymes up to 50%. Phase II has been shown to be low
for people with ADHD or autism. Excess boron interferes with the
metabolism (breakdown and excretion) of phenols. Ritalin, used in the
treatment of ADHD, inhibits the metabolism of coumarins (phenols).
Supplementing boron reduces calcium losses by 30%, but excess boron
increases copper in the body. High copper levels reduce the vitamin
B1, and this reduces oxygen supply to the brain. Excess boron reduces
the vitamin B6 levels in the body also. Boron is found in apples,
pears, grapes, nuts, leafy green vegetables, and legumes. Supplying
these substances, especially apples, pears, and grapes, or their
juices in large amounts to PST deficient children, will cause a build
up of phenols, amines, salicylates, and other toxic substances
normally cleared by PST.

In fact, any chemicals with a high proportion of phenolic groupings
will have this effect, and will enhance the problems referred to
above. Methyl Salicylate: (Salicylic Acid, Wintergreen Oil) is one
such. This phenolic is toxic in moderate concentrations. It is used
in birch beer, chewing gum (in high concentrations), grape, mint,
root beer, sarsaparilla, spice, walnut and wintergreen flavor in
baked goods, beverages, candy, ice cream, ices, syrups, mint-scented
cleaning products, and in perfumery. Symptoms of methyl salicylate
poisoning are acidosis, pulmonary edema and vomiting. This compound
has lethal drug interactions with many substances including
anticoagulants, tricyclic antidepressants, indocin, and methotrexate.
Gallic Acid is another. Gallic Acid is found in food coloring agents
and is, unquestionably, the most important of all phenolics.
Neutralization of gallic acid is the basis of the Feingold Diet,
which eliminates salicylates.

Beef patties containing 30% fat and grilled over mesquite wood had 24
aromatics at a total concentration of 549 g/kg of meat while the same
beef cooked over hardwood (hickory) charcoal had 16 aromatics
representing 68 g/kg. A heavy smoke flavor would produce a higher
concentration of phenols than light smoke. Hamburgers barbecued with
lots of smoke (especially in a covered grill) may be a potential
phenol problem as well as smoked bacon. Smoked bacon cured with
nitrates is even more toxic than phenols by themselves.

Additionally, fruit sugars will feed the candida causing an explosive
overgrowth with increased acetylaldehyde toxins. Candida also
produces arabinose and tartaric acid. Dr. Wm. Shaw of The Great
Plains Laboratory, Inc. thinks that high concentrations of arabinose
may inhibit the liver's production of glucose, causing hypoglycemia
and impairing neurological function. Cheney described two boys
diagnosed as autistic. Their urine test showed high levels of
arabinose and tartaric acid. Tartaric acid looks like malic acid, and
poisons cells by interfering with the Krebs Cycle. Both boys had been
on repeated antibiotics for recurring ear infections, and had not
been autistic until recently. They were about six years old. In these
unusual cases, when the boys were treated with Nystatin™, they both
recovered, and were no longer autistic!

Many coloring materials (porphyrin), whether of natural or synthetic
origin, possess phenolic groupings. For this reason, some
practitioners recommend the removal of all pigmented foods from the
diet (Sara's Diet). This may not be necessary due to the nature of
enzyme activity (the greater the need, the faster it works), but you
must at least eliminate juices (or limit to a little pear juice), and
eliminate all artificial colors and flavors. Avoid "deodorant" soaps
and deodorants containing "triclosan," a chlorophenol. It should be
noted that problems relating to inhibition of cytochrome p450 liver
enzymes (Phase I liver detoxing) are involved with porphyrin in the
foods and supplements named in the above paragraphs. Additionally,
potatoes, tomatoes, and egg plant contain glycoalkaloids, that, even
in small amounts, can greatly slow the metabolism of anesthetic
agents and muscle relaxants, requiring up to 10 times longer to
recover from an anesthetic.

DPT immunization in inbred mice has been shown to result in decreased
synthesis of cytochrome p450, and of phosphosulfotransferase, and of
the messenger RNA necessary for their production. A decrease in
production of the liver enzymes phosphosulfotransferase and the
cytochrome p450 family of enzymes causes failure to break down food
proteins (including gluten and casein) into amino acids. The
resulting intermediates, called peptides, can cross into the blood.
Anything that further inhibits these cytochrome p450 liver enzymes
would compound the problem of toxicity, and further contribute to the
opioid problem. "Treatment of the latter (candida) with conventional
synthetic antifungal agents often causes impairment of liver
detoxification functions, and a decrease in the synthesis of
phosphosulfotransferase, an enzyme necessary to cleave food proteins,
e.g. casein, into smaller easily absorbable peptides."-Dr. Hugh
Fudenberg, MD. Many drugs and opiates interfere with the immune
system. Opiates increase apoptosis (cell suicide) of T-lymphocytes
from the norm of 5% to 30%. Additionally, multiple chemical
sensitivities and liver pain would likely result.

Metallothioneins (MT) are small (short) cysteine-rich proteins that
do more than just help cells detoxify, scavenge free radicals, and
regulate metals. They are involved in cell growth and cell
specialization (differentiation) and homeostasis. Growth factors such
as epidermal growth factor (EGF) cause rat liver cells to grow and
secrete MT. Zinc also stimulated MT and EGF+ zinc made the effect
additive (the EGF effect plus the zinc effect). It is believed that
lots of growth factors that influence liver regeneration play a major
role in regulating MT synthesis and secretion.

William Walsh, senior scientist, Health Research Institute and
Pfeiffer Treatment Center of Naperville, Ill., in his study of 503
children with PDD, Asperger's, and autism, found all but four were
missing MT, which the body needs to bind with toxic metals-like
mercury-so it can be excreted before it damages the brain and gut.
Walsh believes a child who lacks MT may develop any of these
developmental conditions if he gets mercury in his system. This may
explain why some children become autistic after receiving a mercury-
enhanced vaccine. It also explains why autism hits before the age of
3. After that, the brain and the gut have matured enough to withstand
further doses of mercury, although the child may develop ADD and
lesser developmental problems.

Glutathione (along with L-histidine and zinc) is a key resource for
the formation of metallothionein (MT). This molecule prevents
cellular toxicity by creating a stable storage molecule for excesses
of both essential minerals such as copper and zinc, and toxic metals
such as mercury and cadmium. In 1995, Sato et al. reported that
inhibition of glutathione-S-transferase induces decreased expression
of MT. Walsh recently reported that 91% of autistic patients had a
deficiency of metallothionein, and suggested this deficiency is
likely to be genetic, and may be a primary susceptibility factor for
neurotoxicity from heavy metals including vaccinal thimerosal. The
cumulative effects of ingesting mercury can cause brain damage.
Thimerosal, a mercury compound, is used as a preservative in
hepatitis B, diphtheria, pertussis and acellular pertussis, tetanus
and HIB vaccines. Most infants have received a total of 15 doses of
these mercury-containing vaccines by age six months! Studies document
thimerosal as both an allergen and a toxin to sodium channels.

Another interesting connection: Some cysteine is broken down into
taurine and sulfates unless the essential enzyme cysteine dioxygenase
is lacking. In some cases, the sulfur-oxidation of cysteine is
defective. About 30% of the population are slow sulfur-oxidizers and
2% are "nul" S-oxidizers, but in a small study of autistics, 45.8%
were "null" oxidizers! It appears that, in a high percentage of
autistics, oxidation of cysteine is impaired. Slow S-oxidation
appears to be inherited, and has been associated with a number of
disease states, especially rheumatoid arthritis and allergy that are
five times more common in the families of autistic children. One
study of severe food and chemical allergies found 94% had low S-
oxidation capacity and reduced plasma sulfate. It appears, then, that
the PST-troubled kid has numerous allergies, a light-colored stool, a
failure to digest fat from a lack of taurine-formed bile, and is
phenol toxic for want of sulfates. This condition might be indicated
by an elevated copper and mercury reading indicating not enough bile
is being made by the liver. This can sometimes be improved by taking
taurine, and glycine, and the overall condition can be improved by
supplementing sulfates. This seems to be added reason to supplement L-
histidine and molybdenum. The liver should be supported as indicated
elsewhere in this paper. Clinical studies showing that autistic
children with significant allergy problems have elevated
cysteine/sulfate ratios in their blood, and there are other
indications of disordered sulfur amino-acid chemistry.

High plasma cysteine/sulfate ratio indicates a problem of the body
either consuming or wasting sulfate too fast, or not properly forming
sulfate in the enzyme cascade. Cysteine itself is usually in normal
or elevated range, and the problems are concerning the sulfate.
Sulfite oxidase is the enzyme at the end of the metabolic chain from
methionine > cysteine > taurine > sulfate, and is a histidine-
molybdenum enzyme. Supplementing sulfate would surely be a benefit
for the problems directly related to not having enough sulfate for
completing detox and sulfating GAGs. However, some health problems
may be caused by the intermediate products of the impaired sulfur-
oxidation, and not just the lack of sulfate. High plasma or tissue
cysteine, that is, cysteine that is above the normal range,
irrespective of the sulfate levels, is actually quite a different
problem, indicating a failure of the first enzyme step in
metabolizing cysteine. This enzyme, cysteine dioxygenase (CDO), is an
iron-histidine enzyme.

People with high cysteine levels will report discomfort and illness
as a direct result of eating methionine/cysteine rich meats and
plants such as garlic and broccoli. Don't take the glutathione
precursors that contribute directly to the cysteine pool. Both L-
cysteine and whole glutathione do this. It's of interest to note that
cysteine is commonly incorporated into pharmacological preparations
as a stabilizer for peptides such as secretin. Standard chemical
calculations show that a rapid infusion of 1.0 mg cysteine HCl, as
contained in a vial of porcine secretin, will produce a significant
increase in the plasma concentration of cysteine. Since secretin is
not currently given in a weight dependent manner, the lower the
weight of an individual, the greater the increase in cysteine's
plasma concentration. The increase in the cysteine level from one
vial of secretin is negligible in adults, but almost doubles the
plasma concentration in a 30 pound child. This could have very
definite toxic effects for some with a sulfoxidation problem (PST
kids).

Cysteine possesses excitatory neurotransmitter properties, acting
centrally and peripherally at NMDA (N-methyl-D-aspartate) type
glutamate receptors (Parsons et al., 1997). This effect in the CNS
may be responsible for hyperactivity reported by some parents soon
after a child receives secretin. In the presence of bicarbonate ions
in the GI tract (such as the bicarbonate-rich pancreatic fluid
induced by secretin), cysteine becomes a potent excitotoxin (Williams
et al., 1991) which could account for anecdotal reports of loose
stools or diarrhea a few days after a secretin infusion. NAC does not
contribute directly to cysteine toxicity unless you take massive
amounts of it. Around 500 mg/day (adult) you stand to benefit without
significantly increasing risk of cysteine toxicity. The common thread
in all of these failing enzymes is the need for adequate L-histidine.
L-histidine is used by the body in many metal/mineral bearing
enzymes, storage molecules, transport and excretion molecules. People
having metal/mineral enzyme problems, or metal/mineral disregulations
should be looking at supplementing this amino acid in addition to
adjusting their source of minerals such as molybdenum, copper, iron,
zinc, and manganese. In fact, histidine is such a powerful chelator
of heavy metals and minerals that it should probably be used only
under medical supervision lest a deficiency of necessary minerals be
created.

Following the Feingold diet plan will benefit these kids by exclusion
of foods known to include phenols. Salicylates, dyes, sodium
benzoate, BHA, BHT, FD&C yellow dye #5 (tartrazine), vanillin,
eugenol are all phenolic compounds. For a small membership fee, The
Feingold Association will provide a listing of foods to avoid, as
well as a continually updated list of safe foods. Their address is:
Feingold Association of the United States, PO Box 6550, Alexandria,
VA 22306, 1-800-321-3287.

Short of avoiding all these otherwise good foods containing phenols
and malonic acid, what can a PST child do to counter these
undesirable happenings? Take a teaspoon of apple cider vinegar
several times a day as recommended elsewhere in this paper. Two
mothers report that Cranberry juice has reduced or eliminated these
effects, probably by reducing the yeast overgrowth. One should use
Schizandra Chinensis, a very important liver herb. It protects the
liver function and tissue from toxic damage, and has demonstrated a
clinically significant influence on the detoxification process.
Schizandra extract enhances liver glutathione status, and increases
Phase I and Phase II liver enzyme activity. It has no toxic activity.
Glutathione is a substrate for Phase II activity, and particularly
for glutathione-S-transferase (GST), a Phase II enzyme that adds a
glutathione group to Phase I products.

Ambrotose®, Phyt•Aloe®, Dandelion, Ligustrum lucidum, Bovine
colostrum, Shark liver oil, excipients of powdered rice bran,
Schizandra, Green Tea, vitamins A, C, E, undenatured whey, and wheat
grass all produce glutathione effectively without any adverse
toxicity or without messing with the Phase I or Phase II enzyme
activity. A number of foods stimulate the body to produce more of the
Phase II enzymes. These foods have been shown to improve liver
detoxification, and to decrease the risk of developing cancer. They
include members of the cabbage family (crucifers), which includes not
only cabbage but broccoli, cauliflower, bok choy, Brussels sprouts,
green onions, garlic, and kale (all but one are in Phyt•Aloe®). These
vegetables contain compounds called aryl isothiocyanates which
directly stimulate the activity of an enzyme, glutathione S-
transferase, an important component of the Phase II system.
Unfortunately, these same vegetables contain high levels of phenols
which is the toxin not being excreted adequately in PST kids. They
also supply high sulfur that some cannot tolerate, and of course,
some are allergic to them.

Some have found Essaic™ tea helpful in this condition. Dr. Hugh
Fudenberg uses it with his immune-compromised patients, and states
that it heals the endothelial cells of the GI tract and the liver. It
is a proprietary formula of Burdock Root (arctium lappa), Slippery
Elm (ulmas vulva), Sheep Sorrel (rumex acetosella), and Indian
Rhubarb (rheuma palmatum). It probably should be used intermittently
for Burdock is toxic to the liver and peripheral blood mononuclear
cells (PBMC). Sheep Sorrel enhances cytochrome p450 (Phase I) liver
enzymes which will deplete fatty acids, steroids, estrogen,
Prostaglandins, retinoic acid (vitamin A), glycine, and body alcohols
faster, and make many drugs less effective. At least be aware, and if
you use it, supplement fatty acids (Evening Primrose and cod-liver
oil if your child can tolerate them) and glycine, and have the doctor
watch the liver and PBMC functions carefully. For limited periods,
use of herbs that enhance Phase I liver enzyme action would seem
beneficial to those without the PST/sulfoxidation problem. It can be
dangerous for PST kids because the more toxic metabolites of Phase I
action cannot be cleared effectively by PST (Phase II deficient)
types.

Nevertheless, enhancement of Phase I could enhance breakdown of
protein to amino acids, and limit the peptides that upon entering the
blood stream produce opioids. Some nontoxic herbs that do that are
Milk Thistle, Bistort, Ginger, Royal Jelly, and the aforementioned
sheep sorrel. Dandelion is nontoxic, a good chelator and detoxifier,
and has no effect on the Phase I function, thus it may be the best
choice for strengthening the liver function. I strongly advise that
you get the small book "The Liver Cleansing Diet, Love Your Liver and
Live Longer" by Sandra Cabot, MD, and follow this liver friendly
guide to eating. Half the small book consists of recipes. It can make
a world of difference when the liver functions as it should-otherwise
nothing else really works.

Three things that build the liver, even reversing hepatitis, are
Alpha Lipoic acid, Milk Thistle (for short time use), and selenium.

---------------------------------
Still on the topic of PST kids, if you are looking for a phase I AND
II liver support here is a product:

http://www.herbalalternatives.com/mtsxp.html

I suggest browsing through and looking at ALL of their products. I
have ordered the liver support above and one of their immune supports
and plan on trying others. The thing I like best is they are all
liquid drops!

B vitamins and phenol reactions

Biochem Pharmacol 1994 Jun 1;47(11):2087-95

Inhibition of phenol sulfotransferase by pyridoxal phosphate.

Bartzatt R, Beckmann JD.

Department of Internal Medicine, University of Nebraska Medical Center, Omaha 68198-5300.

The biologically abundant cofactor, pyridoxal-5-phosphate (PLP), is a potent inhibitor of bovine phenol (aryl) sulfotransferase (PST). Preincubation of purified enzyme with as little as 1 microM PLP decreased PST activity by 50%. Excess 2-naphthol protected PST from inactivation by PLP, whereas 2-naphthyl sulfate and PAPS were not protective. Although PLP inhibition was apparently competitive with 2-naphthol, a steady-state kinetic Ki value could not be measured due to non-linear Lineweaver-Burk plots in the presence of the inhibitor. Kinetic progress curves revealed that this was due to progressive loss of activity during catalysis. The kinetics of inactivation of PST by PLP were pseudo-first-order and exhibited saturation. The derived KI value for the binding of PLP to PST in the initial reversible step was 23 microM, with a maximal rate of inactivation of 0.077 min(-1). Absorbance spectra of the PST/PLP complex indicated the formation of a Schiff base conjugate, and this is consistent with decreased electrophoretic mobility of the protein-PLP adduct in the presence of dodecyl sulfate only after reduction with borohydride. These results point to the possible regulation of an important detoxification enzyme by a ubiquitous cofactor.

Pyroluria

Pyrrole Disorder

Omega 3s can worsen mental symptoms in bipolar or schizophrenic patients.... if they have a pyrrole disorder. This phenotype is dramatically short of arachidonic acid & giving omega 3 oils aggravates the situation since omega 3 and omega 6 EFA's are in competition for delta 5,6 desaturases. We use red blood cell membrane analysis for EFA's if we suspect this problem. Pyroluric mental patients will usually get worse if given fish oils, DHA, EPA, etc. They thrive on Primrose Oil, a good source of AA and other omega 6s. (June 23, 2003)

Most persons with pyroluria respond very quickly to the B-6, Zn, C, E therapy..... Major improvements are often seen by the 2nd day, and almost always by the end of the first week. The exceptions are: (1) persons with severe mental illness (schizophrenia or bipolar), (2) persons with other significant chemical imbalances, and (3) patients with a major malabsorptive condition. When pyroluria is diagnosed along with another chemical imbalance, I like to track a patient during the first 6-8 weeks to determine which is the dominant imbalance. If major improvement occurs immediately, it's because pyroluria has been corrected. Some patients report a nice early improvement followed by a plateau, and then another advance. Schizophrenic and bipolar pyrolurics usually report some progress after a few weeks, but it may take 3-6 months to get to steady state. The biggest problem with the Kp analysis is getting a proper sample to the lab. The kryptopyrrole molecule is unstable and will disappear rapidly at room temperature or if exposed to bright light. The urine sample must be placed in a freezer immediately after acquisition. Kp can be lost in the freezer if the temperature isn't well below 32 degrees F. We've also learned that exposure to bright light results in breakdown of the Kp molecule. Finally, the sample must be maintained in a frozen condition during shipment. I would greatly suspect any Kp value below 3.0. Usually this means the sample didn't get to the lab in proper condition. With respect to reference levels: We consider a healthy level to be between 4-8 mcg/dL. We consider persons between 10 and 20 to have mild pyroluria, and a good response to treatment is usually reported. Persons exhibiting 20 to 50 mcg/dL have moderate pyroluria, which can be a devastating condition. Persons above 50 mcg/dL have severe pyroluria. Longitudinal testing of pyrolurics has shown that major variations can occur during a day. For example, Arthur Shawcross (famous NY serial killer) had levels ranging from 35 to 203, with higher levels observed during stressful periods in prison. However, he always tested as pyroluric in multiple tests. Stresses, illnesses, injury, etc can be expected to elevate Kp levels. Medical history and review of symptoms are vital to this diagnosis. The major challenge in differential diagnosis of pyroluria is the similarity in symptoms between pyroluria and overmethylation (low blood histamine). Another problem is that symptoms of pyroluria are greatly muted in undermethylated, obsessive/compulsive persons. These persons may be high achievers, with great internal tension..... Persons with pyroluria alone tend to underachieve, partly because of a poor short term memory and associated reading problems. (Nov 10, 2003)

We've obtained hair Zn and plasma Zn levels (simultaneously) about 40,000 times. Low hair zinc correlates beautifully with low plasma levels. However, very elevated Zn in hair nearly always means Zn deficiency and loss plasma Zn levels. Most of the time this involves a Pyrrole disorder which results in very high Zn excretion in urine (and hair). In a healthy person without metal-metabolism problem, only about 4 percent of excreted Zn leaves through the kidneys. [28 Nov 03] Symptoms of pyroluria include (1) stunting of growth, (2) unpleasant body odor, (3) delayed puberty, and (4) skin stretch marks. This family's symptoms are certainly consistent with pyroluria. Pyroluria definitely runs in families. We have a mother in Kane County, IL who has 15 children & all of them tested pyroluric. The mother had a Kp level of over 150 herself

Dopamine and learning

Levodopa: faster and better word learning in normal humans. Knecht S, Breitenstein C, Bushuven S, Wailke S, Kamping S, Floel A, Zwitserlood P, Ringelstein EB. Department of Neurology, University of Munster, Albert-Schweitzer-Strasse 33, D-48129 Munster, Germany. knecht@uni-muenster.de Dopamine is a potent modulator of learning and has been implicated in the encoding of stimulus salience. Repetition, however, as required for the acquisition and reacquisition of sensorimotor or cognitive skills (e.g., in aphasia therapy), decreases salience. We here tested whether increasing brain levels of dopamine during repetitive training improves learning success. Forty healthy humans took 100mg of the dopamine precursor levodopa or placebo daily for 5 days in a randomized double-blind and parallel-group design. Ninety minutes later on each day, subjects were trained on an artificial vocabulary using a high-frequency repetitive approach. Levodopa significantly enhanced the speed, overall success, and long-term retention of novel word learning in a dose-dependent manner. These findings indicate new ways to potentiate learning in a variety of domains if conventional training alone fails.

Neurotransmitters

Abstract

A composition and method for treating Attention Deficit/Hyperactivity Disorder (ADHD) is provided which can be used both with and without ethical drugs now used to treat ADHD. The composition contains dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins (OPC), folic acid, vitamins C, E, B₁₂, B₆, B₅ and beta-carotene and minerals (calcium, magnesium, zinc and selenium). Ethical drugs such as amphetamines, methylphenidate HCl and pemoline are known to control ADHD, but each has significant side effects when used in their therapeutic dose. When combining the composition with such ethical drugs, the amount of the ethical drug can be lowered below a level which causes undesirable side effects which is an important feature. Preferred compositions contain one or more of lecithin, choline, 5-hydroxytryptophan, tyrosine, Reishi Extract, Kava Extract, Gingko, Ginseng and St. John's Wort.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

It is apparent that there is a need for the treatment of ADHD without the serious side effects of the aforementioned known drugs now used for treating ADHD. This invention provides a safe and efficacious combination of natural products which can be used with or without a reduced dosage of known ethical drugs used for ADHD. Dimethylaminoethanol (DMAE) is a natural chemical (found in fish) and has a p-acetamidobenzoate salt formerly prescribed for short attention span and hyperactivity. This drug is now available as an over-the-counter (OTC) nutrient supplement. Unlike most stimulant drugs, which tend to produce a short "up" cycle followed by a quick "come down", DMAE's effects are long lasting and more subtle. People who take DMAE report that after three or four weeks, they feel a mild stimulation continually, without side effects. The quintessential "nootropic" DMAE focuses on specific cortical brain functions associated with the direct intensification of consciousness. Side effects are very rare--high doses may result in insomnia, headache or tense muscles, which disappear if the dose is lowered. No serious adverse effects have been reported with DMAE. DMAE it is hypothesized accelerates the brain's synthesis and turnover of the neurotransmitter, acetylcholine, by redirecting choline synthesis to the cortex. Acetylcholine is the neurotransmitter that the brain uses for short term and long term memory and also helps in concentrating and focusing. Clinical studies including a double blind clinical study comparing DMAE and Ritalin, demonstrated significant test score improvements for both DMAE and Ritalin vs. placebo in ADHD children. DMAE has been shown to increase levels of choline in the brain due to DMAE's superior ability to cross the Blood-Brain Barrier. DMAE has been shown to elevate mood and allow a sounder sleep. DMAE has also been shown to decrease the accumulation of lipofuscin in the brain and to increase attention span and improved concentration. DMAE and derivatives thereof such as its p-acetamido benzoate salt and its bitartrate salt is an important component in the composition of this invention for treating Attention Deficit/Hyperactivity Disorder. Amounts of DMAE of up to 1000 mg, or more, preferably 200-800 mg are used. The brain consists of about 60% fat (lipids). In clinical studies with children with Attention Deficit/Hyperactivity Disorder, supplements of omega-3 fatty acids [eicosapentaenoic acid (EPA), and docosahexanoic acid (DHA)] vs. placebo, have demonstrated improved mood, enhanced clarity of thinking, more serenity and mental clarity of thinking, better concentration and better vision for those taking omega-3 fatty acids. Omega-3 fatty acids (e.g., EPA and DHA; fish oil) are an important component of the composition of the invention and are used in an amount of up to about 1200 mg or more, preferably 200-800 mg. Since the brain contains so much fat (lipids), it is hypothesized the brain has to be protected from free radicals forming "lipid peroxidation" which can cause brain disorders. Antioxidants such as vitamin C, E and A, preferably beta-carotene, improve memory performance and are included in the composition of the invention for this purpose. Vitamin C is used in an amount up to about 1500 mg or more, preferably 200-1000 mg; vitamin E up to about 800 IU or more, preferably 400 IU; and Vitamin A up to about 25,000 IU or more, preferably 10,000-25,000 IU. Recently, U.S. Pat. No. 5,719,178 claimed the use of proanthocyanidins (derived from the conifer bark), an antioxidant, in the treatment of APHD. The general class of oligomeric proanthocyanidins (OPC), which include conifer bark extract, grape seed extract, pine bark extract and the protective phenolic compounds from natural sources including bioflavonoids it is hypothesized can reduce free radical damage causing APHD and are included in the composition of the invention. These "free radical inhibitors" can pass through the Blood-Brain Barrier to protect the brain. OPCs have been shown to possess antihistamine, anti-inflammatory and immune-boosting effects as well as inhibiting the breakdown of the catecholamine neurotransmitters. OPCs increase attention span, increase focus and decrease emotional activity in ADHD persons and are used in the composition of the invention in an amount of about 200 mg or more, preferably 50-150 mg. Faulty neurotransmission is considered the main reason for ADHD. Acetylcholine is involved with learning and memory. Serotonin is involved with mood, emotional balance and impulse control. Catecholamines speed up the rate at which one neuron signals another. It is an important feature of this invention that there be a proper balance between the neurotransmitters for "normal" mental and emotional function. ADHD is a complex disorder involving an unbalance in several neurotransmitters. This invention uses a multi-step approach to fully treat ADHD disorder and the body according to this invention must have "methyl donors" to synthesize the brain chemicals, which accounts for their mood elevating and cognitive effects. Betaine or trimethylglycine, folic acid and vitamin B₁₂ are methyl donors, which are included in the composition of the invention. Betaine is used in an amount up to about 750 mg or more, preferably 100-500 mg. Folic acid is used in an amount up to 1.2 mg or more, preferably 0.4-1 mg and Vitamin B₁₂ up to about 40 mcg or more, preferably 3-30 mcg. In addition to the vitamins mentioned, the body uses vitamin B₅ to form acetylcholine and vitamin B₆ to form serotonin and L-Dopa into Dopamine, which accounts for their effect of increased alertness and mood. These vitamins are included in the composition of the invention. Vitamin B₅ is used up to about 250 mg or more, preferably 50-250 mg and Vitamin B₆ up to about 25 mg or more, preferably 5-25 mg. There are some vital minerals that affect the functioning of the brain. Calcium is a second messenger in neuronal membranes and it acts like a traffic signal for uptake and release of neurotransmitters. A "green light" from calcium permits release of a neurotransmitter into the synaptic intersection and a "red light" halts its passage into the receiving neuron. Calcium regulates the speed, intensity and clarity of every message that passes between brain cells. Magnesium is the second most important mineral in the brain. A study found low magnesium levels in 95% of ADHD children. Supplements of magnesium at a level of 6 mg/lb. of the child showed a decrease in hyperactivity. Zinc is the third most important mineral in the brain, where it acts like an antioxidant and also acts on the surface of the neurons as an electrical "contact" for neurotransmission. Selenium has been shown to protect the integrity of message sending between neurons by preventing free-radical attacks. One or more of these minerals, preferably all, are included in the composition of the invention in amounts up to about 150% of their RDA or more, preferably 100%. Calcium is preferably used at a level of 200 to 1200 mg, magnesium 100 to 500 mg, zinc 5 to 50 mg and selenium 40 to 120 mcg. 5-Hydroxytryptophan (5-HT), the precursor of serotonin, is also included in a preferred composition of the invention in an amount up to 75 mg or more, preferably 25-50 mg. Tyrosine, an amino acid, is a precursor of the catecholamines and used as a food supplement and improves alertness and elevated mood. Tyrosine is included in the composition of the invention in an amount up to 300 mg or more, preferably 50-250 mg. Like omega-3 fatty acids, phospholipids are important for optimal brain health, and are found in high concentrations in the brain. They help the brain cells communicate and influence how well the receptors function. Lecithin is a phospholipid found in certain foods and available as a food implement. Lecithin provides a very available source of choline required for acetylcholine. Lecithin and cytidine 5-diphosocholine (CDP) supplements increase alertness and motivation. Lecithin is used in an amount up to 2000 mg or more, preferably 600-1800 mg. Choline is also included in a preferred composition of the invention in an amount up to 800 mg or more, preferably 100-500 mg. Another important component of a preferred composition of the invention is Reishi extract derived from mushrooms. Reishi extract calms the mind, eases tension, improves memory and sharpens concentration and focus which are all important effects for treating Attention Deficit/Hyperactivity Disorder according to this invention. Reishi extract is used in an amount up to 2000 mg or more, preferably 500-1500 mg. Kava (Piper Methysticum) is a plant grown in the South Pacific and contains kavalactones, which influence a number of brain receptors involved with relaxation and mental clarity. In a study the results showed kava superior to placebo, with improvements in anxiety, mood, tension and fears with increased alertness. With the anxiety that is part of ADHD, kava extract is included in the composition to provide a calming effect and increase concentration. Kava is used in an amount up to 200 mg or more, preferably 50-150 mg. Gingko Biloba extract contains flavonoids and terpene lactones. Gingko improves communication between nerve cells and enhances blood flow to the brain. It also acts as a powerful antioxidant. Ginseng extract has been found to improve blood circulation and provide mental clarity. Researchers have evaluated the cognitive effects of gingko/ginseng. A double blind, placebo controlled study showed improvements in memory and overall cognitive function for those taking both gingko and ginseng and both are in preferred embodiments of the invention. Gingko is used in an amount up to 200 mg or more, preferably 30-120 mg and Ginseng up to about 200 mg or more, preferably 50-150 mg. The herb, St. John's Wort, affects five neurotransmitters in the brain: serotonin, noradrenaline, dopamine, gamma-aminobutyric acid (GABA) and interleukin-6. Because St. John's Wort affects these neurotransmitters, it helps balance them to provide "normality" and is a preferred component in the composition of the invention for treating ADHD in an amount up to about 800 mg or more, preferably 100-600 mg. In the combination of the aforementioned "natural" therapy, with ethical drugs, in addition to amphetamines, methylphenidate HCl, and pemoline, the composition of the invention can be used also with fluoxetine, sertraline, paroxetine, fluoxamine, citalopram, venlafaxine, bupropion, nefazodone and mirtazapien, among others. While the above components as described are the preferred components to be used in the composition of the invention it will be appreciated to those skilled in the art that known derivatives, e.g., salts, may be employed. As set forth hereinabove, it is an important feature of the invention that the components act together to provide a synergistic effect by effecting different pathways of action, i.e., by normalizing the several neurotransmitters and receptor sites responsible for ADHD. While the present invention has been particularly described, in conjunction with a specific preferred embodiment, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description. It is therefore contemplated that the appended claims will embrace any such alternatives, modifications and variations as falling within the true scope and spirit of the present invention.

Child Abuse May Alter Victims' Brain Chemistry, Study Shows

Chicago Tribune, November 1, 2006

CHICAGO - A new study on monkeys raised by abusive mothers suggests that growing up in an abusive household can alter brain chemistry in a way that makes some youngsters prone to mistreating their own children when they grow up.

In other words, abuse is not just something that's learned from living with abusive parents, although that may have an influence, according to authors of the report, published in Thursday's issue of the journal Behavioral Neuroscience.

Suffering through abuse also appears to permanently lower the brain's production of an important regulator of emotions called serotonin, said Dario Maestripieri, the study's lead author and an associate professor at the University of Chicago in comparative human development. Low serotonin can make people more prone to acts of rejection, impulsive aggression and violence.

Of course, most children who were abused do not become abusers themselves. But some do, and the findings of the study may help explain this troubling cycle where victims of abuse later mistreat their own children.

The results emphasize the need for programs to reduce child abuse and to develop behavior-modification strategies for abusive parents. But they also open the door to the development of medications, such as antidepressants, to boost brain serotonin to normal levels in both children and mothers, Maestripieri said.

"This suggests that children who early on have differences in their brain in terms of serotonin could be treated with some of these drugs and maybe these unwanted consequences could be avoided," he said.

Other scientists said that because monkeys are not humans such findings should be interpreted cautiously. Nevertheless, there are enough genetic and biological similarities between the two species, they said, that the results may have important implications for people.

"We know that child abuse is bad for kids and that it's associated with all sorts of mental health outcomes," said University of Wisconsin psychologist Seth Pollak, who was not involved in the research. "But we don't understand how that experience seems to get under children's skin. This emphasis on serotonin seems to really help explain a lot of the behavioral problems that these children have as they grow up."

The findings add to a growing body of scientific evidence showing that nature and nurture interact to produce behavior. Environmental experiences can significantly influence how genes act in the body, affecting behavior, while an individual's genetic makeup can help determine the impact those experiences will have.

Researchers have already documented that humans who have low serotonin levels tend to be more anxious, depressed and impulsive, and earlier studies in rodents linked infant abuse and low serotonin.

Other studies have shown that among monkeys exposed to abuse as infants, those that have a shortened version of the serotonin transporter gene appear to be more vulnerable to experiencing low serotonin levels.

And recent brain scan studies found that people with the short serotonin gene have a more active amygdala, the brain's fear center. A person who has a heightened sensitivity to fear may see threats where none exist and lash out inappropriately.

The study by Maestripieri and his colleagues involved 15 baby rhesus monkeys from a colony housed at Emory University's Yerkes National Primate Research Center. Researchers noted which adult female monkeys displayed abusive behavior to their offspring and which females were nurturing mothers.

When these monkeys became pregnant again, the babies of the abusive mothers were given to the nonabusive females to raise and vice versa. Serotonin levels were measured from the infants' cerebral spinal fluid at birth and at regular intervals into adulthood.

Researchers found that infants raised under abusive conditions tended to develop low serotonin levels and become abusive mothers themselves, even though they were born to nonabusive mothers. Infants born to abusive mothers but raised by nonabusive ones retained normal serotonin levels and were not abusive.

"What's really happening to the infants raised by nonabusive mothers is that they're getting the right input into their brain," said J. Dee Higley of Brigham Young University, who participated in the study, which was funded by the National Institute of Mental Health.

The scientists suspect that low levels of serotonin may serve as a useful survival skill in a threatening situation by making primates more vigilant. But when the level is set low right from birth and stays there, it makes them impulsively aggressive.

"The big news in the new study is that certain patterns of maternal behavior have consequences for their offspring that are not only behavioral but biological and those consequences are possibly lifelong and they appear to be passed on to the next generation," said Stephen Suomi of the National Institute of Child Health and Human Development.

Sumoi did the study showing that monkeys who were raised among other young monkeys instead of by mothers had lower serotonin and became more aggressive if they possessed the shorter serotonin gene. Those with the longer version had higher serotonin levels and basically behaved normally.

(c) 2006, Chicago Tribune. Distributed by Mclatchy-Tribune News Service.

Summary of Biomed Treatments by Jim Adams, Ph.D.

This 28 page document gives an overview of some of the more common biomedical interventions such as dietary changes, gut healing, immune system support, supplementation, and chelation. http://autism.asu.edu/Additional/Summarybiomed07.pdf

Lead inhibits the formation of GABA and increases the concentration of Glutamate/glutamine in the synapse.

Pubmed Laboratory of Pathobiochemistry of the Central Nervous System, Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego str., 02-106 Warsaw, Poland. lidkas@cmdik.pan.pl

Glutamine (Gln), glutamate (Glu) and gamma-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocytic-derived glutamine is the precursor of the two most important neurotransmitters: glutamate, an excitatory neurotransmitter, and GABA, an inhibitory neurotransmitter. In addition to their roles in neurotransmission these neurotransmitters act as alternative metabolic substrates that enable metabolic coupling between astrocytes and neurons. The relationships between Gln, Glu and GABA were studied under lead (Pb) toxicity conditions using synaptosomal fractions obtained from adult rat brains to investigate the cause of Pb neurotoxicity-induced seizures. We have found that diminished transport of [(14)C]GABA occurs after Pb treatment. Both uptake and depolarization-evoked release decrease by 40% and 30%, respectively, relative to controls. Lower expression of glutamate decarboxylase (GAD), the GABA synthesizing enzyme, is also observed. In contrast to impaired synaptosomal GABA function, the GABA transporter GAT-1 protein is overexpressed (possibly as a compensative mechanism).

Furthermore, similar decreases in synaptosomal uptake of radioactive glutamine and glutamate are observed. However, the K(+)-evoked release of Glu increases by 20% over control values and the quantity of neuronal EAAC1 transporter for glutamate reaches remarkably higher levels after Pb treatment. In addition, Pb induces decreased activity of phosphate-activated glutaminase (PAG), which plays a role in glutamate metabolism. Most noteworthy is that the overexpression and reversed action of the EAAC1 transporter may be the cause of the elevated extracellular glutamate levels. In addition to the impairment of synaptosomal processes of glutamatergic and GABAergic transport, the results indicate perturbed relationships between Gln, Glu and GABA that may be the cause of altered neuronal-astrocytic interactions under conditions of Pb neurotoxicity.

Amino Acid Disorders

Amino Acids -- Cofactors and Relationships

Introduction

All tissues have some capability for synthesis of the non-essential amino acids, amino acid remodeling, and conversion of non-amino acid carbon skeletons into amino acids and other derivatives that contain nitrogen. However, the liver is the major site of nitrogen metabolism in the body. In times of dietary surplus, the potentially toxic nitrogen of amino acids is eliminated via transaminations, deamination, and urea formation; the carbon skeletons are generally conserved as carbohydrate, via gluconeogenesis, or as fatty acid via fatty acid synthesis pathways. In this respect amino acids fall into three categories: glucogenic, ketogenic, or glucogenic and ketogenic. Glucogenic amino acids are those that give rise to a net production of pyruvate or TCA cycle intermediates, such as a-ketoglutarate or oxaloacetate, all of which are precursors to glucose via gluconeogenesis. All amino acids except lysine and leucine are at least partly glucogenic. Lysine and leucine are the only amino acids that are solely ketogenic, giving rise only to acetylCoA or acetoacetylCoA, neither of which can bring about net glucose production.

A small group of amino acids comprised of isoleucine, phenylalanine, threonine, tryptophan, and tyrosine give rise to both glucose and fatty acid precursors and are thus characterized as being glucogenic and ketogenic. Finally, it should be recognized that amino acids have a third possible fate. During times of starvation the reduced carbon skeleton is used for energy production, with the result that it is oxidized to CO₂ and H₂O. back to the top

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Essential vs. Nonessential Amino Acids

Nonessential	Essential
Alanine	Arginine*
Asparagine	Histidine
Aspartate	Isoleucine
Cysteine	Leucine
Glutamate	Lysine
Glutamine	Methionine*
Glycine	Phenylalanine*
Proline	Threonine
Serine	Tyrptophan
Tyrosine	Valine

*The amino acids arginine, methionine and phenylalanine are considered essential for reasons not directly related to lack of synthesis. Arginine is synthesized by mammalian cells but at a rate that is insufficient to meet the growth needs of the body and the majority that is synthesized is cleaved to form urea. Methionine is required in large amounts to produce cysteine if the latter amino acid is not adequately supplied in the diet. Similarly, phenyalanine is needed in large amounts to form tyrosine if the latter is not adequately supplied in the diet.

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Amino Acid Biosynthesis

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Glutamate and Aspartate

Glutamate and aspartate are synthesized from their widely distributed a-keto acid precursors by simple 1-step transamination reactions. The former catalyzed by glutamate dehydrogenase and the latter by aspartate aminotransferase, AST.

Reactions of glutamate dehydrogenase

Aspartate is also derived from asparagine through the action of asparaginase. The importance of glutamate as a common intracellular amino donor for transamination reactions and of aspartate as a precursor of ornithine for the urea cycle is described in the Nitrogen Metabolism page. back to the top

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Alanine and the Glucose-Alanine Cycle

Aside from its role in protein synthesis, alanine is second only to glutamine in prominence as a circulating amino acid. In this capacity it serves a unique role in the transfer of nitrogen from peripheral tissue to the liver. Alanine is transferred to the circulation by many tissues, but mainly by muscle, in which alanine is formed from pyruvate at a rate proportional to intracellular pyruvate levels. Liver accumulates plasma alanine, reverses the transamination that occurs in muscle, and proportionately increases urea production. The pyruvate is either oxidized or converted to glucose via gluconeogenesis. When alanine transfer from muscle to liver is coupled with glucose transport from liver back to muscle, the process is known as the glucose-alanine cycle. The key feature of the cycle is that in 1 molecule, alanine, peripheral tissue exports pyruvate and ammonia (which are potentially rate-limiting for metabolism) to the liver, where the carbon skeleton is recycled and most nitrogen eliminated.

There are 2 main pathways to production of muscle alanine: directly from protein degradation, and via the transamination of pyruvate by alanine transaminase, ALT (also referred to as serum glutamate-pyruvate transaminase, SGPT).

glutamate + pyruvate <-------> a-KG + alanine

The glucose-alanine cycle is used primarily as a mechanism for skeletal muscle to eliminate nitrogen while replenishing its energy supply. Glucose oxidation produces pyruvate which can undergo transamination to alanine. This reaction is catalyzed by alanine transaminase, ALT (ALT used to be called serum glutamate-pyruvate transaminase, SGPT). Additionally, during periods of fasting, skeletal muscle protein is degraded for the energy value of the amino acid carbons and alanine is a major amino acid in protein. The alanine then enters the blood stream and is transported to the liver. Within the liver alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The newly formed glucose can then enter the blood for delivery back to the muscle. The amino group transported from the muscle to the liver in the form of alanine is converted to urea in the urea cycle and excreted.

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Cysteine Biosynthesis

The sulfur for cysteine synthesis comes from the essential amino acid methionine. A condensation of ATP and methionine catalyzed by methionine adenosyltransferase yields S-adenosylmethionine (SAM or AdoMet).

Biosynthesis of S-adenosylmethionine, SAM

SAM serves as a precurosor for numerous methyl transfer reactions (e.g. the conversion of norepinephrine to epinenephrine, see Specialized Products of Amino Acids). The result of methyl transfer is the conversion of SAM to S-adenosylhomocysteine. S-adenosylhomocysteine is then cleaved by adenosylhomocyteinase to yield homocysteine and adenosine. Homocysteine can be converted back to methionine by methionine synthase, a reaction that occurs under methionine-sparing conditions and requires N⁵-methyl-tetrahydrofolate as methyl donor. This reaction was discussed in the context of vitamin B₁₂-requiring enzymes in the Vitamins page.

Transmethylation reactions employing SAM are extremely important, but in this case the role of S-adenosylmethionine in transmethylation is secondary to the production of homocysteine (essentially a by-product of transmethylase activity). In the production of SAM all phosphates of an ATP are lost: one as P_i and two as PP_i. It is adenosine which is transferred to methionine and not AMP.

In cysteine synthesis, homocysteine condenses with serine to produce cystathionine, which is subsequently cleaved by cystathionase to produce cysteine and a-ketobutyrate. The sum of the latter two reactions is known as trans-sulfuration.

Cysteine is used for protein synthesis and other body needs, while the a-ketobutyrate is decarboxylated and converted to propionyl-CoA. While cysteine readily oxidizes in air to form the disulfide cystine, cells contain little if any free cystine because the ubiquitous reducing agent, glutathione effectively reverses the formation of cystine by a non-enzymatic reduction reaction.

Utilization of methionine in the synthesis of cysteine

The 2 key enzymes of this pathway, cystathionine synthase and cystathionase (cystathionine lyase), both use pyridoxal phosphate as a cofactor, and both are under regulatory control. Cystathionase is under negative allosteric control by cysteine, as well, cysteine inhibits the expression of the cystathionine synthase gene.

Genetic defects are known for both the synthase and the lyase. Missing or impaired cystathionine synthase leads to homocystinuria and is often associated with mental retardation, although the complete syndrome is multifaceted and many individuals with this disease are mentally normal. Some instances of genetic homocystinuria respond favorably to pyridoxine therapy, suggesting that in these cases the defect in cystathionine synthase is a decreased affinity for the cofactor. Missing or impaired cystathionase leads to excretion of cystathionine in the urine but does not have any other untoward effects. Rare cases are known in which cystathionase is defective and operates at a low level. This genetic disease leads to methioninuria with no other consequences. back to the top

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Tyrosine Biosynthesis

Tyrosine is produced in cells by hydroxylating the essential amino acid phenylalanine. This relationship is much like that between cysteine and methionine. Half of the phenylalanine required goes into the production of tyrosine; if the diet is rich in tyrosine itself, the requirements for phenylalanine are reduced by about 50%.

Phenylalanine hydroxylase is a mixed-function oxygenase: one atom of oxygen is incorporated into water and the other into the hydroxyl of tyrosine. The reductant is the tetrahydrofolate-related cofactor tetrahydrobiopterin, which is maintained in the reduced state by the NADH-dependent enzyme dihydropteridine reductase (DHPR).

Biosynthesis of tyrosine from phenylalanine

Missing or deficient phenylalanine hydroxylase results in hyperphenylalaninemia. Hyperphenylalaninemia is defined as a plasma phenylalanine concentration greater than 2mg/dL (120mM). The most widely recognized hyperphenylalaninemia (and most severe) is the genetic disease known as phenlyketonuria (PKU). Patients suffering from PKU have plasma phenylalanine levels >1000mM, whereas the non-PKU hyperphenylalaninemias exhibit levels of plasma phenylalanine <1000mM. Untreated PKU leads to severe mental retardation. The mental retardation is caused by the accumulation of phenylalanine, which becomes a major donor of amino groups in aminotransferase activity and depletes neural tissue of a-ketoglutarate. This absence of a-ketoglutarate in the brain shuts down the TCA cycle and the associated production of aerobic energy, which is essential to normal brain development.

The product of phenylalanine transamination, phenylpyruvic acid, is reduced to phenylacetate and phenyllactate, and all 3 compounds appear in the urine. The presence of phenylacetate in the urine imparts a "mousy" odor. If the problem is diagnosed early, the addition of tyrosine and restriction of phenylalanine from the diet can minimize the extent of mental retardation.

Because of the requirement for tetrahydrobiopterin in the function of phenylalanine hydroxylase, deficiencies in DHPR can manifest with hyperphenylalaninemia. However, since tetrahydrobiopterin is a cofactor in several other enzyme catalyzed reactions (e.g. see the synthesis of the tyrosine- and tryptophan-derived neurotransmitters as well as nitric oxide in Specialized Products of Amino Acids), the effects of missing or defective DHPR cause even more severe neurological difficulties than those usually associated with PKU caused by deficient phenylalanine hydroxylase activity. back to the top

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Ornithine and Proline Biosynthesis

Glutamate is the precursor of both proline and ornithine, with glutamate semialdehyde being a branch point intermediate leading to one or the other of these 2 products. While ornithine is not one of the 20 amino acids used in protein synthesis, it plays a significant role as the acceptor of carbamoyl phosphate in the urea cycle. Ornithine serves an additional important role as the precursor for the synthesis of the polyamines. The production of ornithine from glutamate is important when dietary arginine, the other principal source of ornithine, is limited.

The fate of glutamate semialdehyde depends on prevailing cellular conditions. Ornithine production occurs from the semialdehyde via a simple glutamate-dependent transamination, producing ornithine. When arginine concentrations become elevated, the ornithine contributed from the urea cycle plus that from glutamate semialdehyde inhibit the aminotransferase reaction, with accumulation of the semialdehyde as a result. The semialdehyde cyclizes spontaneously to D¹pyrroline-5-carboxylate which is then reduced to proline by an NADPH-dependent reductase. back to the top

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Serine Biosynthesis

The main pathway to serine starts with the glycolytic intermediate 3-phosphoglycerate. An NADH-linked dehydrogenase converts 3-phosphoglycerate into a keto acid, 3-phosphopyruvate, suitable for subsequent transamination. Aminotransferase activity with glutamate as a donor produces 3-phosphoserine, which is converted to serine by phosphoserine phosphatase. back to the top

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Glycine Biosynthesis

The main pathway to glycine is a 1-step reaction catalyzed by serine hydroxymethyltransferase. This reaction involves the transfer of the hydroxymethyl group from serine to the cofactor tetrahydrofolate (THF), producing glycine and N⁵,N¹⁰-methylene-THF. Glycine produced from serine or from the diet can also be oxidized by glycine cleavage complex, GCC, to yield a second equivalent of N⁵,N¹⁰-methylene-tetrahydrofolate as well as ammonia and CO₂.

Glycine is involved in many anabolic reactions other than protein synthesis including the synthesis of purine nucleotides, heme, glutathione, creatine and serine. back to the top

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Aspartate/Asparagine and Glutamate/Glutamine Biosynthesis

Glutamate is synthesized by the reductive amination of a-ketoglutarate catalyzed by glutamate dehydrogenase; it is thus a nitrogen-fixing reaction. In addition, glutamate arises by aminotransferase reactions, with the amino nitrogen being donated by a number of different amino acids. Thus, glutamate is a general collector of amino nitrogen.

Aspartate is formed in a transamintion reaction catalyzed by aspartate transaminase, AST. This reaction uses the aspartate a-keto acid analog, oxaloacetate, and glutamate as the amino donor. Aspartate can also be formed by deamination of asparagine catalyzed by asparaginase.

Asparagine synthetase and glutamine synthetase, catalyze the production of asparagine and glutamine from their respective a-amino acids. Glutamine is produced from glutamate by the direct incorporation of ammonia; and this can be considered another nitrogen fixing reaction. Asparagine, however, is formed by an amidotransferase reaction.

Aminotransferase reactions are readily reversible. The direction of any individual transamination depends principally on the concentration ratio of reactants and products. By contrast, transamidation reactions, which are dependent on ATP, are considered irreversible. As a consequence, the degradation of asparagine and glutamine take place by a hydrolytic pathway rather than by a reversal of the pathway by which they were formed. As indicated above, asparagine can be degraded to aspartate. back to the top

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Amino Acid Catabolism

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Glutamine/Glutamate and Asparagine/Aspartate Catabolism

Glutaminase is an important kidney tubule enzyme involved in converting glutamine (from liver and from other tissue) to glutamate and NH₃⁺, with the NH₃⁺ being excreted in the urine. Glutaminase activity is present in many other tissues as well, although its activity is not nearly as prominent as in the kidney. The glutamate produced from glutamine is converted to a-ketoglutarate, making glutamine a glucogenic amino acid.

Asparaginase is also widely distributed within the body, where it converts asparagine into ammonia and aspartate. Aspartate transaminates to oxaloacetate, which follows the gluconeogenic pathway to glucose.

Glutamate and aspartate are important in collecting and eliminating amino nitrogen via glutamine synthetase and the urea cycle, respectively. The catabolic path of the carbon skeletons involves simple 1-step aminotransferase reactions that directly produce net quantities of a TCA cycle intermediate. The glutamate dehydrogenase reaction operating in the direction of a-ketoglutarate production provides a second avenue leading from glutamate to gluconeogenesis. back to the top

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Alanine Catabolism

Alanine is also important in intertissue nitrogen transport as part of the glucose-alanine cycle. Alanine's catabolic pathway involves a simple aminotransferase reaction that directly produces pyruvate. Generally pyruvate produced by this pathway will result in the formation of oxaloacetate, although when the energy charge of a cell is low the pyruvate will be oxidized to CO₂ and H₂O via the PDH complex and the TCA cycle. This makes alanine a glucogenic amino acid. back to the top

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Arginine, Ornithine and Proline Catabolism

The catabolism of arginine begins within the context of the urea cycle. It is hydrolyzed to urea and ornithine by arginase.

Ornithine, in excess of urea cycle needs, is transaminated to form glutamate semialdehyde. Glutamate semialdehyde can serve as the precursor for proline biosynthesis as described above or it can be converted to glutamate.

Proline catabolism is a reversal of its synthesis process.

The glutamate semialdehyde generated from ornithine and proline catabolism is oxidized to glutamate by an ATP-independent glutamate semialdehyde dehydrogenase. The glutamate can then be converted to a-ketoglutarate in a transamination reaction. Thus arginine, ornithine and proline, are glucogenic. back to the top

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Serine Catabolism

The conversion of serine to glycine and then glycine oxidation to CO₂ and NH₃, with the production of two equivalents of N⁵,N¹⁰-methyleneTHF, was described above. Serine can be catabolized back to the glycolytic intermediate, 3-phosphoglycerate, by a pathway that is essentially a reversal of serine biosynthesis. However, the enzymes are different. Serine can also be converted to pyruvate through a deamination reaction catalyzed by serine/threonine dehydratase. back to the top

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Threonine Catabolism

There are at least 3 pathways for threonine catabolism. One involves a pathway initiated by threonine dehydrogenase yielding a-amino-b-ketobutyrate. The a-amino-b-ketobutyrate is either converted to acetyl-CoA and glycine or spontaneously degrades to aminoacetone which is converted to pyruvate. The second pathway involves serine/threonine dehydratase yielding a-ketobutyrate which is further catabolized to propionyl-CoA and finally the TCA cycle intermediate, succinyl-CoA. The third pathway utilizes threonine aldolase. The products of this reaction are both ketogenic (acetyl-CoA) and glucogenic (pyruvate). back to the top

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Glycine Catabolism

Glycine is classified as a glucogenic amino acid, since it can be converted to serine by serine hydroxymethyltransferase, and serine can be converted back to the glycolytic intermediate, 3-phosphoglycerate or to pyruvate by serine/threonine dehydratase. Nevertheless, the main glycine catabolic pathway leads to the production of CO₂, ammonia, and one equivalent of N⁵,N¹⁰-methyleneTHF by the mitochondrial glycine cleavage complex. back to the top

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Cysteine Catabolism

There are several pathways for cysteine catabolism. The simplest, but least important pathway is catalyzed by a liver desulfurase and produces hydrogen sulfide, (H₂S) and pyruvate. The major catabolic pathway in animals is via cysteine dioxygenase that oxidizes the cysteine sulfhydryl to sulfinate, producing the intermediate cysteinesulfinate. Cysteinesulfinate can serve as a biosynthetic intermediate undergoing decarboxylation and oxidation to produce taurine. Catabolism of cysteinesulfinate proceeds through transamination to b-sulfinylpyruvate which then undergoes desulfuration yielding bisulfite, (HSO₃^-) and the glucogenic product, pyruvate. The enzyme sulfite oxidase uses O₂ and H₂O to convert HSO₃^- to sulfate, (SO₄^-) and H₂O₂. The resultant sulfate is used as a precursor for the formation of 3'-phosphoadenosine-5'-phosphosulfate, PAPS.

PAPS is used for the transfer of sulfate to biological molecules such as the sugars of the glycosphingolipids.

Other than protein, the most important product of cysteine metabolism is the bile salt precursor taurine, which is used to form the bile acid conjugates taurocholate and taurochenodeoxycholate.

The enzyme cystathionase can also transfer the sulfur from one cysteine to another generating thiocysteine and pyruvate. Transamination of cysteine yields b-mercaptopyruvate which then reacts with sulfite, (SO₃^2-), to produce thiosulfate, (S₂O₃^2-) and pyruvate. Both thiocysteine and thiosulfate can be used by the enzyme rhodanese to incorporate sulfur into cyanide, (CN^-), thereby detoxifying the cyanide to thiocyanate. back to the top

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Methionine Catabolism

The principal fates of the essential amino acid methionine are incorporation into polypeptide chains, and use in the production of a-ketobutyrate and cysteine via SAM as described above. The transulfuration reactions that produce cysteine from homocysteine and serine also produce a-ketobutyrate, the latter being converted to succinyl-CoA.

Regulation of the methionine metabolic pathway is based on the availability of methionine and cysteine. If both amino acids are present in adequate quantities, SAM accumulates and is a positive effector on cystathionine synthase, encouraging the production of cysteine and a-ketobutyrate (both of which are glucogenic). However, if methionine is scarce, SAM will form only in small quantities, thus limiting cystathionine synthase activity. Under these conditions accumulated homocysteine is remethylated to methionine, using N⁵-methylTHF and other compounds as methyl donors. back to the top

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Valine, Leucine and Isoleucine Catabolism

This group of essential amino acids are identified as the branched-chain amino acids, BCAAs. Because this arrangement of carbon atoms cannot be made by humans, these amino acids are an essential element in the diet. The catabolism of all three compounds initiates in muscle and yields NADH and FADH₂ which can be utilized for ATP generation. The catabolism of all three of these amino acids uses the same enzymes in the first two steps. The first step in each case is a transamination using a single BCAA aminotransferase, with a-ketoglutarate as amine acceptor. As a result, three different a-keto acids are produced and are oxidized using a common branched-chain a-keto acid dehydrogenase, yielding the three different CoA derivatives. Subsequently the metabolic pathways diverge, producing many intermediates.

The principal product from valine is propionylCoA, the glucogenic precursor of succinyl-CoA. Isoleucine catabolism terminates with production of acetylCoA and propionylCoA; thus isoleucine is both glucogenic and ketogenic. Leucine gives rise to acetylCoA and acetoacetylCoA, and is thus classified as strictly ketogenic.

There are a number of genetic diseases associated with faulty catabolism of the BCAAs. The most common defect is in the branched-chain a-keto acid dehydrogenase. Since there is only one dehydrogenase enzyme for all three amino acids, all three a-keto acids accumulate and are excreted in the urine. The disease is known as Maple syrup urine disease because of the characteristic odor of the urine in afflicted individuals. Mental retardation in these cases is extensive. Unfortunately, since these are essential amino acids, they cannot be heavily restricted in the diet; ultimately, the life of afflicted individuals is short and development is abnormal The main neurological problems are due to poor formation of myelin in the CNS. back to the top

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Phenylalanine and Tyrosine Catabolism

Phenylalanine normally has only two fates: incorporation into polypeptide chains, and production of tyrosine via the tetrahydrobiopterin-requiring phenylalanine hydroxylase. Thus, phenylalanine catabolism always follows the pathway of tyrosine catabolism. The main pathway for tyrosine degradation involves conversion to fumarate and acetoacetate, allowing phenylalanine and tyrosine to be classified as both glucogenic and ketogenic.

Tyrosine is equally important for protein biosynthesis as well as an intermediate in the biosynthesis of several physiologically important metabolites e.g. dopamine, norepinephrine and epinephrine (see Specialized Products of Amino Acids).

As in phenylketonuria (deficiency of phenylalanine hydroxylase), deficiency of tyrosine aminotransferase (TAT) leads to hypertyrosinemia and the urinary excretion of tyrosine and the catabolic intermediates between phenylalanine and tyrosine. The adverse neurological symptoms are similar for phenylalanine hydroxylase and TAT deficiencies. In addition, hypertyrosinemia leads to painful corneal eruptions and photophobia.

The first genetic disease ever recognized, alcaptonuria, was demonstrated to be the result of a defect in phenylalanine and tyrosine catabolism. Alkaptonuria is caused by defective homogentisic acid oxidase. Homogentisic acid accumulation is relatively innocuous, causing urine to darken on exposure to air, but no life-threatening effects accompany the disease. back to the top

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Lysine Catabolism

Lysine catabolism is unusual in the way that the e-amino group is transferred to a-ketoglutarate and into the general nitrogen pool. The reaction is a transamination in which the e-amino group is transferred to the a-keto carbon of a-ketoglutarate forming the metabolite, saccharopine. Unlike the majority of transamination reactions, this one does not employ pyridoxal phosphate as a cofactor. Saccharopine is immediately hydrolyzed by the enzyme a-aminoadipic semialdehyde synthase in such a way that the amino nitrogen remains with the a-carbon of a-ketoglutarate, producing glutamate and a-aminoadipic semialdehyde. Because this transamination reaction is not reversible, lysine is an essential amino acid. The ultimate end-product of lysine catabolism is acetoacetyl-CoA

Genetic deficiencies in the enzyme a-aminoadipic semialdehyde synthase have been observed in individuals who excrete large quantities of urinary lysine and some saccharopine. The lysinemia and associated lysinuria are benign. Other serious disorders associated with lysine metabolism are due to failure of the transport system for lysine and the other dibasic amino acids across the intestinal wall. Lysine is essential for protein synthesis; a deficiencies of its transport into the body can cause seriously diminished levels of protein synthesis. Probably more significant however, is the fact that arginine is transported on the same dibasic amino acid carrier, and resulting arginine deficiencies limit the quantity of ornithine available for the urea cycle. The result is severe hyperammonemia after a meal rich in protein. The addition of citrulline to the diet prevents the hyperammonemia.

Lysine is also important as a precursor for the synthesis of carnitine, required for the transport of fatty acids into the mitochondria for oxidation. Free lysine does not serve as the precursor for this reaction, rather the modified lysine found in certain proteins. Some proteins modify lysine to trimethyllysine using SAM as the methyl donor to transfer methyl groups to the e-amino of the lysine side chain. Hydrolysis of proteins containing trimethyllysine provide the substrate for the subsequent conversion to carnitine back to the top

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Histidine Catabolism

Histidine catabolism begins with release of the a-amino group catalyzed by histidase, introducing a double bond into the molecule. As a result, the deaminated product, urocanate, is not the usual a-keto acid associated with loss of a-amino nitrogens. The end product of histidine catabolism is glutamate, making histidine one of the glucogenic amino acids.

Another key feature of histidine catabolism is that it serves as a source of ring nitrogen to combine with tetrahydrofolate (THF), producing the 1-carbon THF intermediate known as N⁵-formiminoTHF. The latter reaction is one of two routes to N⁵-formiminoTHF.

The principal genetic deficiency associated with histidine metabolism is absence or deficiency of the first enzyme of the pathway, histidase. The resultant histidinemia is relatively benign. The disease, which is of relatively high incidence (1 in 10,000), is most easily detected by the absence of urocanate from skin and sweat, where it is normally found in relative abundance.

Decarboxylation of histidine in the intestine by bacteria gives rise to histamine. Similarly, histamine arises in many tissues by the decarboxylation of histidine, which in excess causes constriction or dilation of various blood vessels. The general symptoms are those of asthma and various allergic reactions. back to the top

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Tryptophan Catabolism

A number of important side reactions occur during the catabolism of tryptophan on the pathway to acetoacetate. The first enzyme of the catabolic pathway is an iron porphyrin oxygenase that opens the indole ring. The latter enzyme is highly inducible, its concentration rising almost 10-fold on a diet high in tryptophan.

Kynurenine is the first key branch point intermediate in the pathway. Kynurenine undergoes deamniation in a standard transamination reaction yielding kynurenic acid. Kynurenic acid and metabolites have been shown to act as antiexcitotoxics and anticonvulsives.

A second side branch reaction produces anthranilic acid plus alanine. Another equivalent of alanine is produced further along the main catabolic pathway, and it is the production of these alanine residues that allows tryptophan to be classified among the glucogenic and ketogenic amino acids.

The second important branch point converts kynurenine into 2-amino-3-carboxymuconic semialdehyde, which has two fates. The main flow of carbon elements from this intermediate is to glutarate. An important side reaction in liver is a transamination and several rearrangements to produce limited amounts of nicotinic acid, which leads to production of a small amount of NAD⁺ and NADP⁺

Aside from its role as an amino acid in protein biosynthesis, tryptophan also serves as a precursor for the synthesis of serotonin and melatonin. These products are discussed in Specialized Products of Amino Acids back to the top